Mechanism and pathological significance of cysteine metabolic reprogramming associated with hepatocarcinogenesis

Abstract

Many types of cancer cells have increased demand for specific amino acids, depending on either exogenous supply or upregulated de novo synthesis. Intracellular accumulation of cysteine (Cys) is often observed in cancer cells, which is thought to contribute to the elimination of oxidative stress associated with rapid cell proliferation and/or exposure to anticancer drugs. However, the mechanism of metabolic reprogramming of cysteine during the oncogenesis is not fully understood yet. In this study, we found that the expression levels of genes responsible for cysteine synthesis were downregulated in the hepatocarcinoma-formed tumor tissues implanted in mice. On the other hand, the expression levels of cystine uptake transporter, xCT, were increased in hepatic tumor tissues as compared with healthy liver. The expression of DNA methyltransferase was also increased in hepatocarcinoma tumor tissues and caused DNA methylation of cysteine synthesis genes thereby repressing their expression. Pharmacological inhibition of cysteine synthesis resulted in a temporal decrease in intracellular cysteine contents and upregulation of xCT expression. Therefore, reduction of intracellular cysteine levels appeared to repulsively increase Cys uptake via promoting xCT expression. These findings suggest that the accumulation of Cys in hepatocarcinoma tumor cells results from enhancement of exogenous supply. This metabolic reprogramming may be required for the survival ability of oncogenic transformed cells.